Reactive oxygen species (ROS) have profound influences on cellular homeostasis. In excess, they can potentiate the oxidation of numerous molecules, including proteins, lipids, and nucleic acids, affecting function. Furthermore, ROS-mediated oxidation of proteins can directly or indirectly modulate gene expression via effects on redox-sensitive transcription factors or via effects on phospho-relay-mediated signal transduction. In doing so, ROS impact numerous fundamental cellular processes, and have thus been implicated as critical mediators of both homeostasis and disease pathogenesis. Vascular reduced nicotinamide adenine dinucleotide phosphate oxidase (NOX) is a major contributor of ROS within the lung. The generation of ROS in the pulmonary vasculature has a pivotal role in endothelial cell (EC) activation and function. Alterations in EC phenotype contribute to vascular tone, permeability, and inflammatory responses and, thus, have been implicated in numerous diseases of the lung, including pulmonary hypertension, ischemic-reperfusion injury, and adult respiratory distress syndrome. Thus, although a detailed understanding of NOX-derived ROS in pulmonary EC biology in the context of health and disease is nascent, there is mounting evidence implicating these enzymes as critical modifiers of diseases of the lung and pulmonary circulation. The purpose of this review is to focus specifically on known as well as putative roles for pulmonary EC NOX, with attention to studies on the intact lung.